| Autor: |
Alessandra Cirla, Elena Casale, Nilla Avanzi, Marina Ciomei, Viviana Desperati, Helena Posteri, Eduard R. Felder, Gianluca Papeo, Alessia Montagnoli, Arturo Galvani, Marco Guanci, Daniela Borghi, Antonella Isacchi, Daniele Donati, Sonia Rainoldi, Alessandra Scolaro, Paolo Orsini, Federico Riccardi-Sirtori |
| Rok vydání: |
2019 |
| Předmět: |
|
| Zdroj: |
ACS Medicinal Chemistry Letters. 10:534-538 |
| ISSN: |
1948-5875 |
| Popis: |
[Image: see text] Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD(+) to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.g., Lynparza, Rubraca, Zejula, and Talzenna) used for the treatment of ovarian, breast, and prostate tumors. Efforts in investigating an uncharted region of the previously identified isoindolinone carboxamide series delivered (S)-13 (NMS-P515), a potent inhibitor of PARP-1 both in biochemical (K(d): 0.016 μM) and cellular (IC(50): 0.027 μM) assays. Cocrystal structure allowed explaining NMS-P515 stereospecific inhibition of the target. After having ruled out potential loss of enantiopurity in vitro and in vivo, NMS-P515 was synthesized in an asymmetric fashion. NMS-P515 ADME profile and its antitumor activity in a mouse xenograft cancer model render the compound eligible for further optimization. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
